Neurogenetics最新文献

The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic KRIT1 fragment into a coding exon of KRIT1. This novel structural variant results in a frameshift and was classified as pathogenic. Predictive testing can now be offered to asymptomatic family members. This case expands the known mutation spectrum in FCCM and suggests that, after negative whole exome or gene panel sequencing, whole genome sequencing should be offered as a second-line diagnostic test.

Schinzel-Giedion Syndrome (SGS) is a rare neurodevelopmental disorder caused by pathogenic SETBP1 gain-of-function variants. SGS medical features have been well described. Associated skills critical to quality of life have such as communication, feeding, and motor skills are yet to be characterised. Here we used standardised caregiver report tools to characterise these skills as well as the medical features, in 16 children with SGS (median = 5 years, 7 months, range 6 months to 12.5 years). Vineland-3 scores reflected severe impairment in communication, daily living, socialisation and motor skills. Average receptive and expressive language skills were equivalent to a 0-to-1-month-old. Average motor skills were slightly stronger with age equivalents of 2-months-old for gross motor skills and 4-months for fine motor skills. 13/16 (81%) children could attend to someone's voice, and 15/16 (94%) could make happy vocalisations. One individual (6%) could follow basic instructions. Despite a relatively homogenous phenotype, some children presented with relative strengths when compared to the rest of the cohort. Our expanded phenotype of SGS allows better targeted therapies and supports, highlighting the importance of early feeding intervention and augmentative and alternative communication (e.g., assistive technology for communication). Given the severity of the SGS profile, our data highlight the need for sensitive measurement tools for detecting subtle skill changes in SGS in response to precision medicine interventions.

Type 2 Long QT Syndrome (type 2 LQTS) is a cardiac channelopathy caused by pathogenic variants in the KCNH2 gene, often associated with delayed cardiac repolarization and increased risk of arrhythmias. While its impact is traditionally considered cardiac, emerging studies suggest a potential role of KCNH2 dysfunction in neurogical disorders. We describe monozygotic twin sisters carrying the pathogenic frameshift variant KCNH2 c.2959_2960delCT (p.Leu987Valfs*131; rs748706373), inherited from their asymptomatic father. Clinically, both twins presented with severe language delay, absence of pointing, impaired social interaction, and stereotyped behaviors features consistent with neurogical disorders. Diagnostic diagnostic testing included whole exome sequencing (WES), chromosomal microarray (aCGH), and Fragile X screening. The KCNH2 variant emerged as the sole clinically significant finding. Cardiac evaluation through ECG and 24-hour Holter monitoring revealed no significant QT prolongation or arrhythmic episodes in either the twins or their father. No history of syncope, seizures, or cardiac events was reported. This report supports the variable expressivity and incomplete penetrance of KCNH2 variants in type 2 LQTS and raises the possibility that KCNH2 dysfunction may contribute to neurogical phenotypes manifestations. Causality remains to be established between KCNH2 and neurologic disorders. Though whole-genome sequencing remains to be completed in this pedigree, the potential association between KCNH2 and neurologic disorders is strengthened by the unique monozygotic presentation and the absence of known perinatal complications. Further studies are needed to clarify the association between KCNH2 variants and their contribution to neurological disorders, either through direct neural effects or indirectly via unrecognized perinatal arrhythmic events.

A 40-year-old man with adult-onset spastic-ataxia and tremor showed a leukoencephalopathy with a hypomyelinating pattern on brain MRI. Whole-exome sequencing identified two novel likely pathogenic variants in KIF1C, a gene associated with spastic-ataxia type 2 (SPAX2). This case supports including KIF1C among the causes of adult-onset hypomyelinating leukodystrophies and highlights the diagnostic overlap between spastic-ataxia, hereditary spastic paraplegia, and hypomyelinating leukodystrophies, underscoring the limitations of current nomenclature.

Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA/TTTCA)_n in the MARCHF6 gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing-including exome and genome sequencing-was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic MARCHF6 intronic expansion. The proband harbored one allele with 15 TTTTA repeats and a second allele with a compound expansion of 661 TTTTA and 12 TTTCA repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.

Neurodegenerative disorders pose a significant public health problem. Among these, neurodegeneration with brain iron accumulation syndrome (NBIA) is particularly challenging because even MRI imaging findings can be subtle. Understanding the genetic basis of NBIA is, therefore, crucial for early diagnosis. This study aims to identify pathogenic mutations underlying NBIA in a consanguineous Pashtun family from Pakistan, using Next Generation Sequencing and protein structure modeling. Whole exome sequencing identified a novel pathogenic variant segregating in the family. Bioinformatics tools were employed for assessing the pathogenicity of the variant and 3D structure modelling of the protein. Following the filtration of variants according to the pedigree structure, we identified a novel homozygous variant (NM_001286611.1:c.1460A > C, p.Lys487Thr) in the REPS1 gene in the proband. Subsequent analysis confirmed the segregation of this variant within the family. Identification of this mutation expands our understanding of NBIA genetics and aids in early diagnosis. Stabilizing energy calculations support the impact of this variant on normal portion functioning.

Hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Autosomal recessive HSPs (AR HSPs) are rare and account for approximately 30% of cases, with a higher prevalence in populations with increased consanguinity rates. In this study, we investigated 10 patients diagnosed with AR HSPs and identified pathogenic variants in SPART, FA2H, AP4B1, SPG7, SPG11, CYP2U1, and CYP7B1, with three cases harboring novel variants. Clinical presentations ranged from pure spastic paraplegia to complex phenotypes involving intellectual disability, ataxia, dysarthria, joint abnormalities, and systemic features. Exome sequencing and detailed bioinformatics analyses were employed to identify causative variants, which were classified based on ACMG criteria. The study expands the known genetic spectrum of AR HSPs by reporting previously undescribed variants and providing insight into their potential pathogenic mechanisms. The presence of distinct clinical features in patients with the same genetic variant emphasizes the complexity of genotype-phenotype correlations in HSP. Our findings highlight the importance of genetic testing in early diagnosis and clinical management of HSP, enabling more precise prognostic evaluations and potential therapeutic interventions. Given the high consanguinity rates in certain populations, targeted genetic screening may facilitate early detection and personalized treatment strategies. Further functional studies are needed to elucidate the molecular impact of these novel variants and their role in disease progression, potentially paving the way for future gene-based therapies.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder which seriously affects human health. Worldwide, there has been a significant increase in the incidence rate of PD reported in many populations. Several epigenetic factors are associated with pathogenesis of the PD. SNCA, LRRK2, NURR1, ATP13A2, GSK3B, Parkin, PINK1, DJ-1, and UCHL1are the major genes involved and play a crucial role in the regulatory mechanisms and progression of PD. In this study, a comprehensive approach was used to identify single nucleotide polymorphisms (SNPs) that have a high deleterious effect on the nine proteins mentioned above. In this approach the SNPs of the genes listed above were subjected to more than 13 different computational tools specifically based on sequence, structural and functional analyses. The Frustrometer, NetSurf 3.0, and xProtCAS servers were used to screen the highly deleterious SNPs. Subsequently, modelling of the mutant proteins, structural analysis, STRING analysis, and binding site analysis were performed and compared with wild type proteins. Finally, the highly deleterious missense variants of the SNPs were subjected to molecular docking analysis with FDA-approved drugs for PD. The results indicate that one of the FDA drug compounds exhibits a high binding affinity across all targets. Subsequently, molecular dynamics simulations were performed on the identified compound. These results provide new insights into the genetic variants linked to PD and contribute to the exploration of future research directions in the field of PD.

TSNARE1 regulates the endolysosomal membrane trafficking in cortical neurons and its overexpression might be associated with schizophrenia, but no definitive link to this or any other human pathology has been established yet. Here we present the heterozygous de novo 8q24.3 duplication, involving TSNARE1, in a 38-year-old woman with a juvenile-onset leukodystrophy and with no cerebrospinal fluid positivity. Her 10-year-old healthy daughter harbours the same duplication. These results and data in the literature led us to hypothesize that this unexplained demyelinating disease might represent a novel leukodystrophy linked to overexpression of TSNARE1, however, more data are needed to confirm this hypothesis.

Parkinson's disease (PD) is a complex disorder with contributions by environmental and genetic factors. LRRK2 R1628P is a major genetic risk factor for developing PD in Asian populations. However, the effect of this variant in Kinh Vietnamese remains unclear. This study collected DNA samples of 832 subjects comprising 190 PD patients and 642 control cases, and the LRRK2 R1628P variant was genotyped using an allele-specific oligonucleotide PCR method. The prevalence of the GC genotype of LRRK2 R1628P was significantly higher in the PD group than in the control group, and the LRRK2 R1628P variant showed a significant association with PD with OR = 2.91 (95% CI = 1.50-5.62). LRRK2 R1628P was also found to be associated with PD in subpopulations for males, early-onset, and late-onset. These results emphasize the important genetic contribution of LRRK2 R1628P in the risk of developing PD in the Kinh Vietnamese population.